Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Human Liver Carboxylesterase hCE-1: Binding Specificity for Cocaine, Heroin, and their Metabolites and Analogs

Monica R. Brzezinski, Benjamin J. Spink, Robert A. Dean, Clifford E. Berkman, John R. Cashman and William F. Bosron
Drug Metabolism and Disposition September 1997, 25 (9) 1089-1096;
Monica R. Brzezinski
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Benjamin J. Spink
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert A. Dean
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Clifford E. Berkman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John R. Cashman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William F. Bosron
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Purified human liver carboxylesterase (hCE-1) catalyzes the hydrolysis of cocaine to form benzoylecgonine, the deacetylation of heroin to form 6-acetylmorphine, and the ethanol-dependent transesterification of cocaine to form cocaethylene. In this study, the binding affinities of cocaine, cocaine metabolites and analogs, heroin, morphine, and 6-acetylmorphine for hCE-1 were evaluated by measuring their kinetic inhibition constants with 4-methylumbelliferyl acetate in a rapid spectrophotometric assay. The naturally occurring (R)-(−)-cocaine isomer displayed the highest affinity of all cocaine and heroin analogs or metabolites. The pseudo- or allopseudococaine isomers of cocaine exhibited lower affinity indicating that binding to the enzyme is stereoselective. The methyl ester, benzoyl, and N-methyl groups of cocaine play important roles in binding because removal of these groups increasedKi values substantially. Compounds containing a variety of hydrophobic substitutions at the benzoyl group of cocaine bound to the enzyme with high affinity. The highKi value obtained for cocaethylene relative to cocaine is consistent with weaker binding to the esterase and a longer elimination half-life reported for the metabolite. The spectrophotometric competitive inhibition assay used here represents an effective method to identify drug or environmental esters metabolized by carboxylesterases like hCE-1.

Footnotes

  • Send reprint requests to: Dr. William F. Bosron, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS 405, Indianapolis, IN 46202-5122, wbosron{at}iupui.edu.

  • This work was supported by RO1 DA06836 and fellowships to M.R.B. from T32 AA07462.

  • ↵2 (R)-(+)-pseudococaine is the C2 epimer of (R)-(−)-cocaine, which is found in the leaves ofErythroxylon coca.

  • ↵3 (S)-(+)-cocaine is the unnatural enantiomer of (R)-(−)-cocaine, and (S)-(−)-pseudococaine is the C2 epimer of (S)-(+)-cocaine.

  • Abbreviations used are::
    KM
    Michaelis-Menten constant
    hCE
    human carboxylesterase
    kcat
    turnover number
    Ki
    competitive inhibition constant
    DEA
    N,N-diisopropylethylamine
    DTT
    dithiothreitol
    SDS-PAGE
    sodium dodecyl sulfate-polyacrylamide gel electrophoresis
    • Received March 7, 1997.
    • Accepted June 5, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

 

DMD articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition
Vol. 25, Issue 9
1 Sep 1997
  • Table of Contents
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Human Liver Carboxylesterase hCE-1: Binding Specificity for Cocaine, Heroin, and their Metabolites and Analogs
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Human Liver Carboxylesterase hCE-1: Binding Specificity for Cocaine, Heroin, and their Metabolites and Analogs

Monica R. Brzezinski, Benjamin J. Spink, Robert A. Dean, Clifford E. Berkman, John R. Cashman and William F. Bosron
Drug Metabolism and Disposition September 1, 1997, 25 (9) 1089-1096;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Human Liver Carboxylesterase hCE-1: Binding Specificity for Cocaine, Heroin, and their Metabolites and Analogs

Monica R. Brzezinski, Benjamin J. Spink, Robert A. Dean, Clifford E. Berkman, John R. Cashman and William F. Bosron
Drug Metabolism and Disposition September 1, 1997, 25 (9) 1089-1096;
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Cytochrome P450 4F11 in lung cancer
  • SLC49A4-mediated pyrilamine transport
  • IVIVE of Aldehyde Oxidase-Mediated Clearance
Show more Article

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics